Tumor immunotherapy is a hot spot in tumor therapeutic area for a long time, T cell associated cancer immunotherapy is at the core position. Tumor immunotherapy affects tumors by fully utilizing and mobilizing cytotoxic T lymphocytes in patients with tumors; it may be the most effective and safest way for cancer treatment. At the same time, tumor escape is a huge obstacle faced by tumor immunotherapy, in which cancer cells promote rapid growth of the tumor via its inhibitory effect on the immune system.
There is extremely complex relationship between tumor immune escape mechanism and body's immune response to tumors. In early stage of tumor immunotherapy, tumor-specific killer T cells have biological activity, but lose the killing function in the late stage of tumor growth. So tumor immunotherapy is to utmostly enhance the response of the patient's own immune system to the tumor. The key of tumor immunotherapy is not only to activate the response of the existing immune system, but also to maintain the duration and intensity of the response of the immune system.
Human T-cell activation in vivo is implemented by a two-signaling-pathway system which not only needs to submit a MHC-antigen peptide via antigen-presenting cells to T cells to provide a first signal, but also requires a series of costimulatory molecules to provide a second signal, and then T cells exhibit normal immune response. This double-signaling system plays a vital role in balance of the immune system, and strictly regulates the different immune responses stimulated by endogenous and exogenous antigens. The absence of a second signal provided by co-stimulatory molecules will result in no response or sustained-specific T cell immune response, consequently leading to tolerance. Therefore, the second signal pathway plays a key regulatory role in the whole process of the immune response.
Programmed death-1 (PD-1), found in 1992, is a protein receptor expressed in T cell surface, and is involved in cell apoptosis. PD-1 belongs to CD28 family, exhibits 23% homology in amino acid sequence with cytotoxic T lymphocyte antigen 4 (CTLA-4), but is mainly expressed in activated T cells, B cells and myeloid cells, which is different from CTLA. PD-1 has two ligands, PD-L1 and PD-L2 respectively. PD-L1 is mainly expressed in T cells, B cells, macrophages, and dendritic cells (DC), and the expression is upregulated in the activated cells. The expression of PD-L2 is mainly limited to antigen-presenting cells, such as activated macrophages and dendritic cells.
New studies have detected high expression of PD-L1 protein in human tumor tissues such as breast cancer, lung cancer, stomach cancer, intestinal cancer, renal cancer, melanoma and others, and the expression levels of PD-L1 is closely related to clinical condition and prognosis of patients. For PD-L1 inhibits T cell proliferation through the second signaling pathway, blocking the binding of PD-L1/PD-1 becomes a very promising target in tumor immunotherapy field.
Currently, there are several multinational pharmaceutical companies engaged in monoclonal antibodies against PD-1, which maximize the self immune response of patients against tumor by blocking the binding of PD-L1/PD-1, and sequentially achieve the killing purpose against tumor cells, such as WO2009114335. In the clinical results of BMS' and Merck's PD-1 monoclonal antibodies, certain response rate have been observed in non-small cell lung cancer, melanoma and renal carcinoma, and the response rate exhibited prominently high relevance with PD-L1 expression in tumors, which suggested that PD-1 antibody exerts a positive effect on tumors.
The present invention provides a PD-1 antibody with high affinity, high selectivity, and high biological activity.